Cytokine responses in acute and persistent human parvovirus B19 infection

The aim of this study was to characterize the proinflammatory and T helper (Th)1/Th2 cytokine responses during acute parvovirus B19 (B19) infection and determine whether an imbalance of the Th1/Th2 cytokine pattern is related to persistent B19 infection. Cytokines were quantified by multiplex beads immunoassay in serum from B19-infected patients and controls. The cytokine responses were correlated with B19 serology, quantitative B19 DNA levels and clinical symptoms. In addition to a proinflammatory response, elevated levels of the Th1 type of cytokines interleukin (IL)-2, IL-12 and IL-15 were evident at time of the initial peak of B19 viral load in a few patients during acute infection. This pattern was seen in the absence of an interferon (IFN)-gamma response. During follow-up (20-130 weeks post-acute infection) some of these patients had a sustained Th1 cytokine response. The Th1 cytokine response correlated with the previously identified sustained CD8+ T cell response and viraemia. A cross-sectional study on patients with persistent B19 infection showed no apparent imbalance of their cytokine pattern, except for an elevated level of IFN-gamma response. No general immunodeficiency was diagnosed as an explanation for the viral persistence in this later group. Neither the acutely infected nor the persistently infected patients demonstrated a Th2 cytokine response. In conclusion, the acutely infected patients demonstrated a sustained Th1 cytokine response whereas the persistently infected patients did not exhibit an apparent imbalance of their cytokine pattern except for an elevated IFN-gamma response.     

Detection of IgE anti-parvovirus antibodies in human breast milk

Breast milk is a complex fluid, rich in nutrients and non-nutritional bioactive components, including antimicrobial factors, immunoglobulins, cytokines, and anti-inflammatory substances. Although IgE is implicated in viral immunity, its role in breast milk in parvovirus B19 immunity has not been studied. Total immunoglobulin levels of IgE, IgG, and IgE anti-parvovirus B19 antibodies were determined by ELISA and Western blot analysis in breast milk and in sera from a mother and her nursing infant (female, 10 mo). For specific IgE protein determination, breast milk was fractionated by chromatography on G-100 Sephadex; 3 peaks were collected and separated by SDS PAGE. The levels of total IgE in breast milk and its fractions were low (<2.4 ng/ml), and those of maternal and infant serum were negligible (18 and 4.3 IU/ml, respectively). Nevertheless, the breast milk and maternal and infant sera contained IgE anti-parvovirus B19 antibodies, even though the infant was never infected with parvovirus B19. Total serum levels of maternal IgG were within the normal range and those of infant IgG were low (473 mg/dl); total IgG in breast milk was not determined. Maternal serum contained some detectable IgG anti-parvovirus antibodies that were not present in infant serum or breast milk. Total maternal and infant serum levels of IgM and IgA were within the normal ranges. The presence of IgE anti-parvovirus B19 antibodies in breast milk suggests that IgE anti-viral antibodies are transmitted in breast milk and may provide protective responses in nursing children.     

The disease progression in the keratin 14 IL-4-transgenic mouse model of atopic dermatitis parallels the up-regulation of B cell activation molecules, proliferation and surface and serum IgE

We have previously characterized the keratin 14 interleukin-4-transgenic (IL-4-Tg) mouse model of atopic dermatitis as a chronic pruritic inflammatory skin disease typified by skin infiltration of inflammatory cells and early up-regulation of Th2 cytokines and late surge of Th1 cytokines. In the present study, we examined the involvement of B cells. Systematic examinations of the following immunological parameters on B cells were carried out in non-Tg control mice and in IL-4-Tg mice at before disease onset and early and late disease stages so that we could determine the immunological sequence of events leading to the disease development: surface expressions of IA/IE, activation and costimulatory molecules, proliferation under LPS or IgM stimulation, quantification of cell surface and serum IgE, IgG1, and IgG2a. Our results showed that as the disease progresses from before onset to early disease and to late disease, there is a parallel increase in surface markers of B cell activation (IA/IE, CD44, CD69, CD80 and CD86), in B cell proliferation, and in cell surface and serum IgE. Significant increases of Th2-driven serum IgG1 and IgE in early disease was followed by significant increase of Th1-driven IgG2a in late disease. Importantly the significant increases of activation molecule (IA/IE), proliferation (to LPS), and surface IgE on B cells of the IL-4-Tg mice precedes the up-regulation of serum IgE and disease onset. These data suggest that activated B cells may play a role in atopic dermatitis disease development by up-regulating serum IgE concentration, which serves as a marker of disease onset.     

Circulating cytokines and chemokines in acute symptomatic parvovirus B19 infection: negative association between levels of pro-inflammatory cytokines and development of B19-associated arthritis

The aim of the study was to characterise the profile and clinical correlates (arthritis, rash, and fatigue) of cytokines, chemokines, and other mediators in symptomatic acute parvovirus B19 infection. Serum was examined from cases of acute B19 infection (as defined by serum anti-B19 IgM positivity) (n = 84), and in normal persons (n = 43) for B19 markers (serum B19 antibodies and DNA), rheumatoid factor (RF), and antinuclear antibody (ANA). A panel of cytokines/chemokines was measured in duplicate using the Bioplex Protein Array system (BioRad Hemel Hempstead, UK). These included interleukin-1 beta (IL-1 beta), IL-4, IL-5, IL-6, IL-8, IL-13, tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), macrophage chemoattractant protein-1 (MCP-1), granulocyte-monocyte colony stimulating factor (GM-CSF), transforming growth factor-beta1 (TGF-beta 1), endothelin-1 (ET-1), and neopterin. Acute symptomatic infection was characterised by specific IgG positivity (83%), serum B19 DNA positivity (96%), and raised levels of IL-4, IL-6, IL-8, TNF-alpha, IFN-gamma, MCP-1, GM-CSF, TGF-beta 1, and ET-1. Patients with acute B19-associated arthritis were found to have lower levels of IL-6, TNF-alpha, and GM-CSF than patients without arthritis, while those with rash had lower levels of TGF-beta 1. It is concluded that cytokine levels following acute symptomatic infection with parvovirus B19 indicate a state of immune activation. The profile of circulating mediators may provide insights into the possible pathogenesis of particular clinical manifestations of this infection.     

人细小病毒B19阳性再障患者一些细胞因子变化

为探讨人细小病毒Ｂ１９（ＨＰＶＢ１９） 所致再生障碍性贫血（ＡＡ） 的免疫学改变, 应用酶联免疫吸附试验检测ＡＡ 患儿血清白细胞介素８ 和６ （ＩＬ ８、ＩＬ ６）、肿瘤坏死因子α（ＴＮＦ α） 及干扰素α（ＩＦＮ α） 水平。结果： ＡＡ 患儿上述各免疫指标水平均显著高于正常对照组（Ｐ＜ ０－０１ 或Ｐ＜ ０－０５） 。其中ＨＰＶＢ１９ 阳性ＡＡ 组ＩＬ ８ 水平亦高于ＨＰＶＢ１９ 阴性组, 而ＩＬ ６、ＴＮＦ α及ＩＦＮ α两组间无差异。对ＨＰＶＢ１９ ＡＡ组作直线相关分析显示, ＩＬ ８ 与ＴＮＦ α和ＩＦＮ α呈正相关, ＴＮＦ α与ＩＬ ６ 呈正相关（ｒ 分别为０－５６５ 、０－６０３ 及０－８６０, Ｐ＜ ０－０１） 。提示： ＨＰＶＢ１９ 所致ＡＡ 患儿有明显的免疫功能紊乱, 多种细胞因子, 特别是ＩＬ ８ 可能在其免疫病理机制中起一定作用。     

In vivo administration of IL-18 can induce IgE production through Th2 cytokine induction and up-regulation of CD40 ligand (CD154) expression on CD4+ T cells

IL-18 is considered to be a strong cofactor for CD4+ T helper 1 (Th1) cell induction. We have recently reported that IL-18 can induce IL-13 production in both NK cells and T cells in synergy with IL-2 but not IL-12, suggesting IL-18 can induce Th1 and Th2 cytokines when accompanied by the appropriate first signals for T cells. We have now found that IL-18 can act as a cofactor to induce IL-4, IL-10 and IL-13 as well as IFN-gamma production in T cells in the presence of anti-CD3 monoclonal antibodies (mAb). IL-18 can rapidly induce CD40 ligand (CD154) mRNA and surface expression on CD4+ but not CD8+ T cells. The administration of IL-18 alone in vivo significantly increased serum IgE levels in C57BL/6 (B6) and B6 IL-4 knockout mice. Furthermore, the administration of IL-18 plus IL-2 induced approximately 70-fold and 10-fold higher serum levels of IgE and IgG1 than seen in control B6 mice, respectively. IgE and IgG1 induction in B6 mice by administration of IL-18 plus IL-2 was eliminated by the pretreatment of mice with anti-CD4 or anti-CD154, but not anti-CD8 or anti-NK1.1 mAb. These results suggest that IL-18 can induce Th2 cytokines and CD154 expression, and can contribute to CD4+ T cell-dependent, IL-4-independent IgE production.     

Chronic parvovirus B19 infection induces the production of anti-virus antibodies with autoantigen binding properties

Human parvovirus B19 infection in adults shows some clinical features similar to those found in autoimmune connective tissue diseases. To better clarify the relationship between viral infection and autoimmunity, we have evaluated the ability of anti-parvovirus antibodies to specifically recognize autoantigens in ten patients with chronic symmetric arthritis resembling rheumatoid arthritis or with recurrent episodes of arthritis and cutaneous manifestations and persistence of specific IgM antibodies against B19 parvovirus. We synthetized a 24-amino acid immunodominant peptide corresponding to a part of the virus protein 1 and virus protein 2 overlapping region. The peptide has been used to test patients' sera at different time points with an enzyme-linked immunosorbent assay (ELISA) and to purify anti-virus antibodies by affinity chromatography on a peptide-Sepharose column. Eluted immunoglobulins recognized the B19 peptide in both direct and competitive ELISA. Affinity-purified anti-parvovirus antibodies were then tested on a panel of autoantigens including human keratin, collagen type II, thyreoglobulin, single-strand (ss)DNA, cardiolipin and ribonucleoprotein antigen Sm. Eluted antibodies specifically recognized keratin, collagen type II, ssDNA and cardiolipin. Autoantibody activity was not detected in the immunoglobulin fraction after complete removal of anti-peptide antibodies and in antibodies eluted from normal donors. Epstein-Barr virus-transformed cell clones obtained from two subjects produced antibodies which simultaneously recognize the viral peptide and several autoantigens. To further confirm the role of the virus in inducing an autoantibody response, eight BALB/c mice were immunized with the viral peptide coupled to a carrier protein. Autoantibody activity against keratin, collagen II, cardiolipin and ssDNA was detected in six of the eight mice which developed a strong anti-virus response. Together, these data indicate that B19 parvovirus may be linked to the induction of an autoimmune response.     

Critical function of the CD40 pathway in parvovirus B19 infection revealed by a hypomorphic CD40 ligand mutation

Parvovirus B19-induced chronic anemia has been associated with failure to mount an effective neutralizing antibody response. We describe an adolescent male with a 13-year history of parvovirus B19-induced anemia as the primary manifestation of X-linked hyper IgM immunodeficiency (XHIM). This patient, whose serum IgG concentration was at the low end of the normal range and who mounted IgG antibody responses to T cell-dependent antigens, suffered from a nonsense mutation (R11 --> X) in the CD40 ligand (CD40L) gene. This resulted in low-level expression of a mutant CD40L predicted to lack the cytoplasmic domain. Intravenous immunoglobulin therapy alone or in combination with interferon gamma, given in the context of impaired Th1 cytokine production, suppressed but did not eradicate the infection. These results highlight the critical function of the CD40/CD40L pathway in parvovirus B19 infection and suggest that subtle defects in this pathway may underlie cases of chronic parvovirus B19 infection atypical of XHIM.     

Seroprevalence of parvovirus B19 antibodies and evidence of viremia among Nigerian patients with sickle cell anemia

Clinical, biochemical and molecular evidence for the sickle cell anemia (SCA) crisis in Nigerian patients arising from parvovirus b19 infection remains inadequate. This study determined the prevalence and correlates of anti-parvovirus b19 antibodies in a population of SCA patients and non-SCA healthy controls in Lagos, Nigeria. In this prospective cross-sectional study, we enrolled 73 confirmed SCA patients from 5 district hospitals in Lagos and 81 sex and age-matched non-SCA healthy controls. Serum sample from each study participant was screened for anti-parvovirus b19 by ELISA and PCR techniques. Standard biomedical assays were also done. Anti-parvovirus b19 IgM and IgG antibodies were detected in 22 (14.3%) and 97 (62.9%) of the 154 sera screened, 13 (17.8%) and 45 (61.6%) in SCA patients; 9 (11.1%) and 52 (64.2%) in non-SCA controls. The overall seronegativity rate was 19.5%. Parvovirus B19 DNA was found in 2 (11.1%) of the 18 IgM seropositive SCA serum samples screened. On the whole, parvovirus b19 infection was more commonly asymptomatic in non-SCA controls but caused significant elevation in liver enzymes in infected SCA patients (P < 0.05). The risk of acute parvovirus b19 infection increased 65 times during unsteady state among the SCA patients. Although no deaths of infected patients were recorded during the study, age below 12 years, hospitalization and overcrowded environment were risk factors for infection. We conclude that parvovirus b19 is common in SCA patients, incurring greater susceptibility to infections.     

Investigation on the Maternal-Infantile Infection with Human Parvovirus B19

With the investigations on pregnant women and newbornsinfected withToxoplasma, rubella virus, cytomegalovirus,herpes simplex virus (TORCH), it was found that humanparvovirus B19 (B19 virus), which belongs to the familyParvoviridae and the genus Erythrovir…     

The prevalence and persistence of human parvovirus B19 infection in thalassemic patients

Human parvovirus B19 infection was studied in 60 thalassemic patients in Thailand. Seroprevalence, persistence of parvovirus B19 and their genotypes were identified in blood samples. Prevalence of anti-parvovirus B19 IgG and DNA found in thalassemic patients were 38% and 13%, respectively. Anti-parvovirus B19 IgM could be detected in 4% of these positive anti-parvovirus B19 IgG patients. The seroprevalence and parvovirus B19 DNA in patients with a history of blood transfusion were not significantly higher than those without such a history (44% vs. 34% and 20% vs. 9%, respectively). Phylogenetic analysis of NS1 nucleotide sequences of three parvovirus B19 samples revealed that they were parvovirus B19 genotype 1. They showed low genetic diversity from prototype (Au) strain. We concluded that acute and chronic persistent parvovirus B19 infection were found in the thalassemic Thai patients. Chronic persistence of parvovirus B19 infection might play important clinical role in thalassemic patients because of the high prevalence of parvovirus B19 DNA. Blood transfusion had no significant influence to increase the prevalence of parvovirus B19 infection in thalassemic patients.     

IL-10 is predominantly produced by CD19(low)CD5(+) regulatory B cell subpopulation: characterisation of CD19 (high) and CD19(low) subpopulations of CD5(+) B cells

IL-10 production by CD19(+)CD5(+) B cells was investigated, by determining the expression levels of CD19, a classical B cell marker. Peripheral mononuclear cells were stained with fluorescence-conjugated anti-CD5, anti-CD19, anti-IL-10, and Annexin V. Interestingly, IL-10-producing B cells were found to be localised within the CD19(low)CD5(+) B cell subset. Apoptotic changes were also observed mainly in CD19(low) cells among B cells. Thus, CD5(+) B cells should be classified as CD19(high) and CD19(low) cells, and the immunological significance of CD19 for the IL-10 production by CD5(+) B cells requires further studies.     

Frequency of IL-10+CD19+ B cells in patients with prostate cancer compared to patients with benign prostatic hyperplasia

BackgroundThe function of the immune system in prostate cancer (PC) might promote carcinogenesis. PC is a common cancer in men. Regulatory B cells (Bregs) are a new subtype of B cells that have suppressive roles in the immune system. Interleukin-10 (IL-10) is a dominant mediator of immune suppression released by Bregs.ObjectiveThe purpose of this research was to examine the frequency of CD19+IL10+ B cells and IL-10 mRNA expression in patients with PC compared to patients with benign prostatic hyperplasia (BPH).MethodsForty paraffin tissue samples from patients with PC and 32 paraffin tissue samples from patients with BPH were entered in this study. The immunohistochemistry staining was used to evaluate the pattern expression of CD19 and IL-10 markers. IL-10 mRNA expression in fresh tissue was determined by real time-polymerase chain reaction (RT-PCR).ResultsThe frequency of CD19+IL-10+ B cells and IL-10 mRNA expression in PC patients were significantly higher than patients with BPH. Also, there was no meaningful relationship between the frequency of IL-10+CD19+ B cells and gleason scores in patients with PC.ConclusionsOur findings suggested that frequency of IL-10+CD19+ B cells correlates with progressive stage of PC.     

Prevalence and association of human parvovirus B19V with hepatitis B and C viruses in Nigeria

Co-infection of parvovirus B19 with hepatitis B virus has been found in patients with acute and chronic hepatitis. The clinical significance of parvovirus B19 in hepatitis B co-infected patients is still controversial. In this study parvovirus B19 antibodies and DNA were investigated in serum samples from 76 patients with HBV infection, 17 with HBV/HCV co-infection and 44 healthy controls. In the sera from patients with HBV infection, anti-B19V IgM and IgG antibodies were detected in 24/76 (32%) and 25/76 (33%), in 6/17 (35%) and 8/17 (47%) of HBV/HCV co-infected patients, and in 14/44 (32%) and 12/44 (12%) of a non-hepatitis healthy controls, respectively. B19V DNA was detected in 8/76 (11%) of patients with HBV infection and in 3/17 (18%) of patients with a HBV/HCV co-infection, and in 4/44 (9%) healthy controls. The occurrence of parvovirus B19 DNA was significantly higher in patients with symptomatic HBV 4/20 (20%) compared to asymptomatic HBV carrier 4/56 (7%) (P<0.05). Ten of the positive B19V DNA sequences belonged to B19V genotype 1 while two belonged to genotype 3. The results of this study showed a significant difference in the prevalence of parvovirus B19 DNA in symptomatic HBsAg positive as compared to asymptomatic HBsAg positive individuals; however, the conclusion that parvovirus B19 infection increased the frequency of liver disease was not supported. Long-term longitudinal studies are, however, required to determine the synergistic effect of parvovirus B19 infection in HBV or HBV and HCV co-infected persons.     

Chronic autoimmune thrombopenia/neutropenia in a boy with persistent parvovirus B19 infection

OBJECTIVE: We report an 11-year-old boy presenting with splenomegaly, chronic thrombocytopenia and concordant neutropenia. RESULTS: In contrast to autoantibodies against platelets, there were no detectable neutrophil-specific autoantibodies present in this patient. Extensive serologic investigations revealed increased IgM- and IgG-antibody titers against parvovirus B19. A nested polymerase chain reaction (PCR) showed parvovirus B19-specific sequences in the patient's bone-marrow cells but not in the serum. Specific antibodies against the structural proteins VP1 and VP2 in addition to those against non-structural protein NS1 of parvovirus B19 were detected by Western blot analysis. Thrombocytopenia and neutropenia responded to immunosuppressive therapy and subsequent splenectomy, the latter being necessary due to severe side-effects of steroid medication. CONCLUSION: Autoimmune thrombocytopenia/neutropenia may have been triggered and/or sustained by a chronic parvovirus B19 infection. Patients with this very rare disorder should be screened for this virus.     

Inhibition of eosinophil infiltration into the mouse peritoneal cavity by a traditional Chinese medicine, Bu-zhong-yi-qi-tang (Japanese name: Hochu-ekki-to)

Our previous study showed that the serum level of antigen-specific IgE antibodies in primary response was decreased by a traditional Chinese medicine, Bu-zhong-yi-qi-tang (Japanese name; Hochu-ekki-to, HOT). In this study, we examined inhibition of secondary IgE response and of eosinophil infiltration by HOT. BALB/c mice were intraperitoneally immunized with aluminum hydroxide adsorbed with DNP-KLH (DNP-KLH + alum) on day -14 and on day 0. In mice treated with HOT daily from day -14, the serum level of antigen-specific IgE antibodies after the secondary immunization was significantly decreased compared to that in mice not treated with HOT. Eosinophils increased in number after 6 and 24 hr, and CD4+ T cells in the peritoneal cavity increased in number 24 hr after the secondary immunization. HOT suppressed accumulation of eosinophils and CD4+ T cells in the peritoneal cavity. Furthermore, HOT suppressed the numbers of IL-4- and IL-5-producing cells 24 hr after the secondary immunization, but did not inhibit the number of IFN-gamma-producing cells. HOT also suppressed IL-5 mRNA expression. Furthermore, HOT also inhibited antigen-induced late-phase reaction (LPR) in the skin. These results suggested that HOT exhibited anti-allergic effects mainly by inhibiting Th2 cell responses.     

IMMUNE RESPONSES IN AUTOIMMUNE HEPATITIS: EFFECT OF PREDNISONE AND AZATHIOPRINE TREATMENT: CASE REPORT

The role of the immune response in autoimmune hepatitis has not been studied before and after prednisone and azathioprine treatment. Distributions of blood lymphocytes (CD4+, CD8+, CD19+, CD23+, CD16/56+), levels of serum immunoglobulins (IgM, IgG, IgE, IgA) and cytokines (IFN-γ, IL-4, IL-12, TNFα ) were studied in a child (f/14 y/o) with autoimmune hepatitis before and after prednisone (20 mg/d) and azathioprine (50 mg/d) treatment (nephelometry, UniCAP Total IgE Fluoroenzymeimmunoassay, flow cytometry, cytokine ELISA). Patient was studied for 0-2.5 yrs; treatment was initiated 12 weeks post diagnosis. Numbers of CD4+ T cells increased (50%), while CD19+ and CD23+ cells decreased (>50%) post treatment; other lymphocyte subsets were unaffected by treatment. Serum IgG and IgE levels decreased (>50%) after treatment; serum IgM and IgA were within normal range and were not affected by treatment High levels of IFN-γ (5-23 pg/ml) were initially detected in serum, which decreased after treatment (<0.1 pg/ml). Furthermore, low levels of IL-4 (0.2 pg/mL) were detected before treatment, which were not detected after treatment (<0.1 pg/ml). In contrast, before treatment, IL-12 and TNFα were not detected in serum; however after treatment the levels of IL-12 and TNFα dramatically increased. Prednisone and azathioprine treatment decreased total serum IgG, IgE, IFN-γ and IL-4 levels, and blood CD19+ and CD23+ cells; however serum IL-12, TNFα and blood CD4+ T cells increased with treatment. Understanding immunomodulation in autoimmune hepatitis will provide better insight and mechanisms of this disease and may tailor more effective therapeutic intervention.     

婴幼儿呼吸道疾病B淋巴细胞状况分析

用流式细胞术测定婴幼儿哮喘、婴幼儿肺炎、婴幼儿急性上呼吸道感染患儿外周血淋巴细胞CD19、CD19+ CD2 3+ 表达 ,用化学发光免疫法测定其血清总IgE水平 ,以探索婴幼儿呼吸道疾病时B淋巴细胞及其活化状况。结果表明 ,婴幼儿哮喘组CD19+ 、CD19+ CD2 3+ 表达、血清总IgE水平明显增高 ,婴幼儿肺炎、婴幼儿急性上呼吸道感染无升高 ;婴幼儿哮喘组CD19的表达阳性率和绝对值分别与CD19+ CD2 3+ 表达阳性率和绝对值均呈正相关。提示婴幼儿哮喘存在明显的B淋巴细胞数量增多及活化异常 ,婴幼儿肺炎和婴幼儿急性上呼吸道感染B淋巴细胞状况无明显改变     

CD19-deficient mice exhibit poor responsiveness to oral immunization despite evidence of unaltered total IgA levels, germinal centers and IgA-isotype switching in Peyer's patches

CD19 exhibits a critical role as a response regulator in B cells, influencing activation, differentiation and survival. Accordingly, CD19-deficient mice largely lack B-1 cells, and their conventional B-2 cells are poor responders to thymus-dependent antigen. Since both B-1 and B-2 cells may contribute to the total intestinal IgA production, we investigated whether lack of CD19 negatively affected mucosal immunity. We found that CD19(-/-) mice have near normal total IgA levels in serum and gut mucosa and, contrary to systemic lymphoid tissues, Peyer's patches (PP) had germinal centers to which also IgA+ B cells localized. However, the mice demonstrated severely impaired responses to oral immunization with keyhole limpet hemocyanin plus cholera toxin adjuvant. Mucosal responses to oral immunization were significantly more impaired than systemic responses. Despite normal specific IL-4 production, a selective defect in Th2-regulated B cell isotypes was observed, with poor or no mucosal IgA, low serum IgG1 and no IgE, but intact serum IgA and IgG2a production. Ex vivo experiments revealed strongly inhibited CD40-stimulated proliferation and IgA differentiation in CD19-deficient PP B cells. Taken together, an impaired CD40 responsiveness selectively affected Th2, but not Th1, coordinated B cell responses. The CD19(-/-) mice provide compelling evidence for the differential regulation of serum and mucosal IgA immunity.